GB1594179A - Introduction of a carbonyl group into a cyclohexene ring - Google Patents

Description

PATENT SPECIFICATION ( 11) 1 594 179

( 21) Application No 4218/78 ( 22) Filed 2 Feb 1978 ( 31) Convention Application No2704406 ( ( 32) Filed 3 Feb 1977 in ( 33) Federal Republic of Germany (DE) ( 44) Complete Specification published 30 July 1981 tl ( 51) INT CL 3 C 07 C 175/00 ( 52) Index at acceptance C 2 V 1

( 54) INTRODUCTION OF A CARBONYL GROUP

INTO A CYCLOHEXENE RING ( 71) We, BASF AKTIENGESELLSCHAFT, a German Joint Stock Company of 6700 Ludwigshafen, Federal Republic of Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following Statement: 5

The present invention relates to a process for introducing an allylpositioned carbonyl group into a cyclohexene ring.

The oxidation of retinol, retinal and vitamin A-acid methyl ester with manganese (IV) dioxide so as to bring about oxidation in the 4-position of the cyclohexene ring has been disclosed in Tetrahedron Letters, 1972, pages 1, 823 10 1,825 and J Chem Soc 1957, pages 4,909-4,912 This process requires up to a 20fold excess of oxidizing agent, based on substrate, and the yields obtained vary greatly, due to the varying activity of the manganese (IV) dioxide, which in turn is a function of its conditions of manufacture.

It has also been disclosed that an allyl-positioned methylene group in the 15 cyclohexene ring can be oxidized by means of metaperiodate For example, retinal (German Laid-Open Application DOS 2,064,495), /3-carotin and retrodehydrocarotin (German Patent 1,793,308) can be respectively converted to 4-oxoretinal or canthaxanthin by means of sodium metaperiodate in the presence of a halogen or of an oxide of a metal selected from groups Ia, Via, VI Ia and VIII of the 20 periodic table Essential disadvantages of this process are the high cost of the oxidizing agent, and the low yield, varying from 17 to 38 %, when manufacturing canthaxanthin.

We have now found that an allyl-positioned carbonyl group may be introduced into a cyclohexene ring by oxidizing a cyclohexene derivative of the formula 25 H-C CH 3 C 113 X,3 where X is hydrogen or hydroxyl and Y is a polyenyl radical, with a halogen(V)oxyacid or a salt of such an acid in the presence of bromine or iodine or of an oxide of a transition element selected from groups V, VI, VII and VIII of the periodic table, as the catalyst, and in the presence of an inert diluent or solvent, in an acid 30 medium at from 0 to 100 C.

Essential advantages of the process according to the invention are that the reaction takes place rapidly, the yield is improved and the oxidizing agents are readily accessible and cheap.

Suitable starting compounds of the formula I are cyclohexene derivatives 35 which carry allyl-positioned methylene or hydroxymethylene groups and have a polyenyl radical as the substituent Y, as well as /3-ionone.

The end products are polyene compounds of the formula II H 3 c-3 L 5111 X c 1 LZ I 1,594,179 2 where Y is a polyenyl radical, preferably of the formula C Tl T CH 3 CH: CEI-C-CH t C 3 = e C CH= C R where m is 0, 1 or 2 and N is 0, 1, 2, 3 or 4 and R is methyl, formyl, carboxyl, alkanoyl of 2 to 4 carbon atoms, alkoxycarbonyl of 2 to 4 carbon atoms, alkoxymethyl of 2 to 4 carbon atoms, alkanoyloxymethyl of 3 or 4 carbon atoms,/3 5 acetylvinyl, /3-formylvinyl or /3 ( 2,6,6 trimethyl cyclohex I en 3 onyl) vinyl, with the proviso that m and N are not both 2 if R is /3 ( 2,6,6 trimethylcyclohex 1 en 3 onyl) vinyl.

Examples of starting materials are /3-ionone for the manufacture of 4-oxo/3ionone, vitamin A acetate for the manufacture of 4-oxo-vitamin A acetate, /3-apo 10 8 '-carotinal for the manufacture of 4-oxo-p 3-apo-8 '-carotinal, /3-apo12 '-carotinal for the manufacture of 4-oxo-/3 p-apo-12 '-carotinal, /3-apo-4 'carotinic acid ethyl ester for the manufacture of 4-oxo-/3-apo-4 '-carotinic acid ethyl ester, /3apo-8 '-carotinic acid ethyl ester for the manufacture of 4-oxo-/3-apo-8 '-carotinic acid ethyl ester, citranaxanthin for the manufacture of 4-oxo-citranaxanthin, torularhodinaldehyde 15 for the manufacture of 4-oxo-torularhodinaldehyde, torularhodine methyl ester for the manufacture of 4-oxo-torularhodine methyl ester, /3-apo-2 'carotinal for the manufacture of 4-oxo-/3-apo-2 '-carotinal, torularhodine for the manufacture of 4-oxo-torularhodine, torulene for the manufacture of 4-oxo-torulene, 7 ', 8 ' dihydro 7 ' apo /3 carotin 8 ' one for the manufacture of 4 oxo 7 ',8 ' 20 dihydro 7 ' apo /3 carotin 8 ' one and all trans 1,10 di ( 2,6,6 trimethylcyclohex 1 enyl) 3,8 dimethyl deca 1,3,5,7,9 pentaene for the manufacture of all trans 1,10 di ( 2,6,6 trimethylcyclohex 1 en 3 onyl) deca 1,3,5,7,9 pentaene.

The starting materials are oxidized in the presence of an inert diluent or 25 solvent The use of solutions in readily volatile diluents or solvents which are waterimmiscible is preferred.

Suitable diluents and solvents include aliphatic chlorohydrocarbons, e g.

chloroform, methylene chloride, 1,1-dichloroethane, 1,2-dichloroethane, 1, 1,2trichloroethane, 1,1,2,2-tetrachloroethane, 1,2-dichloroethylene and 1,1, 2 30 trichloroethylene, aromatic hydrocarbons, e g benzene, toluene, nitrobenzene and chlorobenzene, dialkyl ethers, e g diethyl ether and di-n-propyl ether, and carbon disulfide Particularly suitable solvents are chloroform, methylene chloride and 1,2dichloroethane Mixtures of these diluents or solvents may also be used.

The oxidizing agents used are halogen(V)-oxyacids or salts of these acids They 35 include chloric acid, bromic acid, iodic acid and the alkali metal salts, alkaline earth metal salts and ammonium salts of these acids, especially chloric acid and bromic acid and their alkali metal salts The oxidizing agents are advantageously added to the reaction mixture in the form of their aqueous solutions of from 5 to 50 % O strength by weight The molar ratio of oxidizing agent to starting material is 40 generally from 1:1 to 20:1, preferably from 1:1 to 10:1 A more than 20fold molar excess of oxidizing agent has no effect on the reaction.

The oxidation is catalyzed by bromine or iodine or by an oxide of a transition element selected from groups V, VI, VII and VIII of the periodic table Examples of suitable catalysts are vanadium pentoxide, molybdenum trioxide, tungsten trioxide, 45 manganese dioxide, nickel oxide and osmium tetroxide Preferred catalysts are bromine, iodine and osmium tetroxide Iodine is a particularly suitable catalyst.

The catalyst is added undiluted or in solution, for example in the solvent which has been used for the solution of the starting material or in water The catalyst may also advantageously be formed in situ; for example iodine is formed from sodium 50 iodide under the reaction conditions The amount of catalyst is advantageously from 0 1 to 25 % by weight, based on starting material Larger amounts of catalyst have no additional effect on the reaction.

The reaction is carried out at from 0 to 100 C, preferably from 10 to 70 C The reaction temperature may be varied within wide limits, the upper limit being 55 determined by the heat stability of the starting material or of the end product.

The reaction takes place in an acid medium, ranging from strongly acid to p H 7 The preferred p H range is from 1 to 3 The desired p H may be obtained by means of acids, e g sulfuric acid, hydrochloric acid or acetic acid, or of buffer mixtures.

The reaction time is generally from I to 24 hours, depending on the selected 60 conditions.

In order to prevent further oxidation of the end products by atmospheric oxygen, the reaction may be carried out under an inert gas atmosphere Gases which are suitably inert under the reaction conditions are argon, neon, helium, carbon dioxide and especially nitrogen.

S In a preferred embodiment of the process, an aqueous solution of the oxidizing 5 agent is added, under an inert gas atmosphere, to a solution or slurry of the starting material in a diluent or solvent which is inert under the reaction conditions and is water-immiscible The aqueous phase is then brought to the desired p H by means of an acid or a buffer mixture The catalyst is added as a solid or solution and the two phases are mixed by stirring until a suitable analytical method, e g thin layer 10 chromatography, indicates complete conversion.

The organic phase is then stripped off and crude end product is isolated therefrom either by stripping off the solvent or by precipitation Normally, it suffices to boil the crude material in a solvent which does not dissolve the end product, e g in an alcohol, in order to obtained a crystalline end product The 15 reaction product may or may not be purified by chromatography.

The Examples which follow illustrate the process according to the invention.

EXAMPLE I

9.6 g ( O 05 mole) of f-ionone are dissolved in 250 ml of chloroform 26 5 g ( 0 25 mole) of sodium chlorate and 1 125 g of sodium iodide in 100 ml of water are 20 added The mixture is acidified with 0 11 ml of concentrated sulfuric acid and stirred for 24 hours at 450 C It is then allowed to cool, the phases are separated and chloroform phase is washed first with saturated sodium bicarbonate solution and then with water After stripping off the solvent, 9 1 g of a dark oil, containing 64 % by weight of 4-oxo-f-ionone, remain Fractional distillation in a high vacuum gives 25 4.1 g of an oil which solidifies slowly After recrystallization from a 1:1 mixture of methanol and water, the product has a melting point of 51-520 C and proves identical, in all properties, with the product obtained by reacting 3ionone with Nbromosuccinimide and then carrying out an oxidation with manganese(IV) dioxide (J Chem Soc ( 1951), 1074) 30 EXAMPLE 2

1 g of 4-hydroxy-p-apo-8 '-carotinic acid methyl ester, prepared as described in U.S Patent 3,068,257, is dissolved in 30 ml of chloroform A solution of I g of sodium chlorate and 0 1 g of osmium tetroxide in 10 ml of water is added and the mixture is stirred at 100 C It is acidified with 1 drop of acetic acid and the phases 35 are agitated for 24 hours They are then separated, the organic phase is washed with water and dried, and the solvent is distilled off under reduced pressure The partially crystalline residue is refluxed with 50 ml of heptane for 60 minutes After cooling and standing for 24 hours, 0 61 g of 4-oxo-p-apo-8 '-carotinic acid methyl ester is filtered off 40 EXAMPLE 3

0 1 mole of vitamin A acetate is introduced into 850 ml of methylene chloride.

A solution of 79 5 g of sodium chlorate ( 0 75 mole) and 1 125 g ( 7 51 mmoles, corresponding to 7 5 mole %, based on vitamin A acetate) of sodium iodide in 300 ml of water is added After cooling to 100 C, the mixture is acidified with O 015 g of 45 concentrated sulfuric acid and is stirred at l OOC for 18 hours The phases are then separated and the organic phase is washed with 400 ml of saturated sodium bicarbonate solution and then with water After drying and concentrating, an oily raw material which contains 57 % by weight of 4-oxo-vitamin A acetate is obtained.

The ketone can be obtained pure by column chromatography 50 220 Mc/s-f H-NMR spectrum (CDC 13); a values:

1.4 S ( 6 H); 1 8 S ( 3 H); 2 5 t ( 2 H); 6 1-6 7 m (SH) Mass spectrum: m/e: 282 (M-CH 3 COOH); 43 (H 3 C-CO) IR spectrum: bands at 1,735 cm' and 1,655 cm'.

EXAMPLE 4 55 g of p-apo-12 '-carotinal are dissolved in 100 ml of 1,2-dichloroethane A solution of 4 g of sodium chlorate and 0 3 g of sodium iodide in 80 ml of water is added The mixture is heated to the reflux temperature, stirred and acidified with I ml of aqueous hydrochloric acid which contains 3 mg of hydrogen chloride After 4 hours, the mixture is allowed to cool to room temperature After separating the 60 phases, the organic solution of the carotinoid is washed with water, with a dilute 1,594,179 sodium carbonate solution and again with water After drying over magnesium sulfate, the solvent is evaporated off under reduced pressure A viscous red oil remains, from which 3 45 g of crystalline 4-oxo-/3-apo-12 '-carotinal are obtained by boiling in 20 ml of isobutanol, cooling and filtering after 24 hours.

220 Mc/s H-NMR spectrum (CDCI 3); 8 values: 5 1.25 S ( 6 H); 1 9 S ( 6 H); 2 1 d ( 6 H); 2 55 t ( 2 H); 6 2-7 3 m ( 911) ; 9 5 S (IH) IR spectrum: band at 1,650 cm-' UV spectrum: Almax= 415 nm in cyclohexane; E 1 = 2,360.

EXAMPLE 5

10 g of /-apo-8 '-carotinic acid ethyl ester are dissolved in 250 ml of methylene 10 chloride and the solution is cooled to 10 C 8 g of sodium chlorate and 0 2 g of sodium iodide, dissolved in 100 ml of water, are added When both phases have reached 10 C, 0 12 ml of acetic acid dissolved in 20 ml of water is added dropwise in the course of 60 minutes After stirring for 10 hours at 10 C, half the starting material has reacted A further 0 2 g of sodium iodide and 0 12 ml of acetic acid 15 dissolved in 20 ml of water are added and the mixture is stirred for a further 12 hours at room temperature It is worked up as described in Example 2 and the crude material, in 30 ml of ethanol, is refluxed for 10 hours After cooling, 6 15 g of 4-oxo/p-apo-8 '-carotinic acid ethyl ester, of melting point 142-143 C, are filtered off after 24 hours 20 220 Mc/s-1 H NMR spectrum (CDC 13); 8 values:

1.15 S ( 6 H); 1 3 S ( 3 H); 1 95 S ( 12 H); 2 5 t ( 2 H); 4 2 q ( 2 H); 6-6 7 m (I IH); 7 25 d ( 1 H) US spectrum: Amax= 450 nm in cyclohexane; E'= 2,220.

EXAMPLE 6 25 g of p/3-apo-4 '-carotinic acid ethyl ester are oxidized as described in Example 4 The mixture is stirred for 10 hours at 10 C and worked up without adding further catalyst or acid Ater boiling in ethanol, and cooling, 7 96 g of 4-oxo-/apo-4 'carotinic acid ethyl ester are isolated.

220 Mc/s 'H-NMR spectrum (CDCI 3); 8 values: 30 1.2 S ( 6 H); 1 3 t ( 3 H); 2 5 t ( 2 H); 4 2 g ( 2 H); 6 1-6 7 m ( 14 H); 7 25 d (IH) US spectrum: A,,max= 481 nm in cyclohexane; E,= 2,310.

EXAMPLE 7 g of 3-apo-8 '-carotinal are dissolved in 200 ml of 1,2-dichloroethane 12 g of sodium chlorate and 0 5 g of sodium bromide in 100 ml of water are added and the 35 mixture is heated to the reflux temperature 10 ml of aqueous hydrochloric acid containing 3 mg of hydrogen chloride are added dropwise in the course of 60 minutes, whilst stirring Refluxing is continued for 60 minutes and the mixture is then cooled After separating the phases, the organic phase is repeatedly washed with water and then concentrated 30 ml of isopropyl alcohol are added to the oily 40 crude product and the mixture is refluxed for 2 hours After 24 hours, 7 14 g of crystalline 4-oxo-/-apo-8 '-carotinal, of melting point 152 C, are filtered off.

220 Mc/s 'H-NMR spectrum (CDCI 3): 8 values:

1.2 S ( 6 H); 1 8 S ( 8 H); 2 0 S ( 9 H); 2 5 t ( 2 H); 6 15-6 95 m ( 12 H); 9 45 S (IH) UV spectrum: Amax= 449 nm in cyclohexane; E,= 2,750 45 Polyene compounds of the formula II.

H-.C C 0 .here Y is 21 FT ('2 R where m is I or 2 and N is 0, 1, 2, 3 or 4 and R is methyl, formyl, carboxyl, alkanoyl 50 of 2 to 4 carbon atoms, alkoxycarbonyl of 2 to 4 carbon atoms, alkoxymethyl of 2 to r.'594 179 c -'2 1,594,1/79 5 4 carbon atoms, alkanoyloxymethyl of 3 to 4 carbon atoms, /3-formylvinyl or /3 ( 2,6,6 trimethylcyclohex I en 3 onyl) vinyl, with the provisos that N is not O if R is formyl, carboxyl or methoxycarbonyl and m and N are not both 2 if R is /3 ( 2,6,6 trimethylcyclohex 1 en 3 onyl) vinyl, are new.

They are red and can be used as dyes for foodstuffs and cosmetics They can also 5 serve as valuable intermediates for the manufacture of carotinoids E g the 4-oxoaldehydes (of 25 or 30 carbon atoms) may be used for the manufacture of echinenone.

The Examples which follow illustrate the use of the compounds.

EXAMPLE 8 10

A lipophilized starch is prepared from rice starch by means of an aqueous solution of dimethyl-stearyl-benzylammonium chloride 4-Oxo-/3-apo-8 'carotinic acid ethyl ester is then worked into the starch in the conventional manner The pasty slurry obtained is dried and ground to give a powder, which is added to a talc composition, giving a talc with a hue resembling skin color 15 EXAMPLE 9

A 10 % strength, cold water-soluble, dry powder formulation of 4-oxo-P 3apo-8 'carotinal is prepared in the conventional manner I g of this dye formulation is dissolved in 10 ml of water and added to the raw materials required for 10 liters of ice cream, e g cream, milk, sugar, gelatin and flavoring A deep red ice cream is 20 obtained.

EXAMPLE 10 mg of a dye formulation containing 10 % of 4-oxo-p 3-apo-4 '-carotinic acid ethyl ester are added to a blancmange powder which suffices for one liter of finished blancmange, and the powder is then used in the conventional manner by 25 stirring or boiling with milk.

EXAMPLE 11

0.5 g of a dry powder containing 10 % of 4-oxo-/3-apo-12 '-carotinal is dissolved in 10 ml of water and the solution is homogeneously incorporated into I kg of white toothpaste of a conventional composition Alternatively, the same dye formulation 30 may be added to the raw materials which are dissolved in water or pasted with water A red toothpaste is obtained.

EXAMPLE 12

3.98 g of 4-oxo-/3-apo-12 '-carotinal ( 4-oxo-aldehyde of 25 carbon atoms) are added to a solution of 5 62 g of /3 ionylidene ethyl triphenyl phosphonium 35 bisulfate in 67 ml of absolute dimethylformamide The mixture is cooled to -20 C and at this temperature 0 92 g of ammonia gas is introduced in the course of one hour, whilst stirring The mixture is then allowed to come to room temperature, 34 ml of water and 40 ml of heptane are added and the batch is stirred briefly at 40 C.

The lower phase is then separated off until the carotinoid present at the interface is 40 encountered, and 80 ml of water are added The mixture is stirred at 40 C and the lower phase is again separated off The upper phase is then washed twice with a mixture of 30 ml of methanol and 20 ml of water and is dehydrated azeotropically, and the heptane is distilled off until the residual volume is 10 ml The residue is refluxed for 10 hours When it has cooled, 80 ml of heptane are added and the 45 mixture is filtered 3 76 g of a finely crystalline residue comprising 97 %o of all-transechinenone are obtained.

Claims (1)

1. WHAT WE CLAIM IS:-

   1 A process for introducing an allyl-positioned carbonyl group into a cyclohexene ring, wherein a cyclohexene derivative of the formula 50 H 3 C CH 3 CHM 5 X I where X is hydrogen or hydroxyl and Y is a polyenyl radical, is oxidized with a halogen(V)-oxyacid or a salt of such an acid in the presence of bromine or iodine or s RA A I ova 6 1,594,79 of an oxide of a transition element selected from groups V, VI, VII and VIII of the periodic table, as the catalyst, and in the presence of an inert diluent or solvent, in an acid medium at from 0 to 100 C.

   2 A process as claimed in claim 1, wherein the oxidation is carried out with an alkali metal salt of chloric acid or of bromic acid 5 3 A process as claimed in claim I or 2, wherein the oxidation is carried out in the presence of iodine as the catalyst.

   4 A process as claimed in claim 3, wherein the catalyst is formed in situ.

   A process as claimed in any of claims I to 4, wherein the oxidation is carried out in the presence of an inert diluent or solvent which is waterimmiscible 10 6 A process as claimed in any of claims 1 to 4, wherein the oxidation is carried out in the presence of an aliphatic chlorohydrocarbon as the diluent or solvent.

   7 A polyene compound of the formula IC CIAH.3 0 So w;here Y is 15 CH=Cr =C'l CE=CH-CH=Cwhere m is I or 2 and N is 0, 1, 2, 3 or 4 and R is methyl, formyl, carboxyl, alkanoyl of 2 to 4 carbon atoms, alkoxycarbonyl of 2 to 4 carbon atoms, alkoxymethyl of 2 to 4 carbon atoms, alkanoyloxymethyl of 3 to 4 carbon atoms, /3-formylvinyl or /3 ( 2,6,6 trimethylcyclohex I en 3 onyl) vinyl, with the provisos that N is 20 not 0 if R is formyl, carboxyl or methoxycarbonyl, and m and N are not both 2 if R is /3 ( 2,6,6 trimethylcyclohex I en 3 onyl) vinyl.

   8 A process as claimed in any of claims I to 6, wherein Y in the formula of the starting material I has the meaning given in claim 7.

   9 A process as claimed in any of claims I to 6 or 8, wherein the starting 25 material is /3-ionone, vitamin A acetate, /3-apo-8 '-carotinal, /3-apo-12 '-carotinal, /3apo-4 ' or -8 '-carotinic acid ethyl ester, citranaxanthin, torularhodinaldehyde, torularhodine methyl ester, /3-apo-2 '-carotinal, torularhodine, torulene, 7 ',8 ' dihydro 7 ' apo /3 carotin 8 ' one or all trans 1,10 di ( 2,6,6 trimethymethylcyclohex I enyl) 3,8 dimethyl deca 1,3,5,7,9 pentaene 30 A process as claimed in claim I carried out substantially as described in any of the foregoing Examples I to 12.

   11 A polyene compound of the formula II when obtained by a process as claimed in any of claims I to 6 or 8 to 10.

   J Y & G W JOHNSON, Furnival House, 14-18, High Holborn, London, WCIV 6 DE, Chartered Patent Agents, Agents for the Applicants.

   Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa, 1981 Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.

   1,594,179 A